Download Chemical Information Review Document for Arbutin [CAS No. 497-76-7] and

Chemical Information Review Document
for
Arbutin [CAS No. 497-76-7] and
Extracts from Arctostaphylos uva-ursi
Supporting Nomination for Toxicological Evaluation by the
National Toxicology Program
January 2006
Prepared by:
Integrated Laboratory Systems, Inc.
Research Triangle Park, NC
Under Contract No. N01-ES-35515
Prepared for:
National Toxicology Program
National Institute of Environmental Health Sciences
National Institutes of Health
U.S Department of Health and Human Services
Research Triangle Park, NC
http://ntp.niehs.nih.gov/
Abstract
Arbutin is found in the dried leaves of a number of different plant species including bearberry
(Arctostaphylos uva-ursi). The leaves and leaf extracts from uva ursi are used in non-prescription
medicinal products mainly to treat urinary tract infection, cystitis, kidney stones, and as a diuretic. The
active component, arbutin, is converted to hydroquinone (HQ) which has antimicrobial, astringent, and
disinfectant properties. Arbutin is also an inhibitor of melanin formation and is use in some skinlightening products. It is rapidly metabolized and excreted in rats as unchanged arbutin and in humans as
HQ, HQ glucuronide, and HQ sulfate. HQ induced renal tubule adenomas in male rats and liver
adenomas and thyroid gland follicular cell hyperplasia in mice. It was negative in the Ames assay but
induced mutations and micronuclei in mouse L5178Y lymphoma and chromosome aberrations and sisterchromatid exchange in Chinese hamster ovary cells. Side effects reported from the ingestion of dried uva
ursi leaves included nausea and vomiting, irritability, insomnia, and an increased heart rate. Extremely
high doses can cause ringing in the ears, shortness of breath, convulsions, collapse, and delirium. Uva
ursi has also been linked with albuminuria, hematuria, and urine cast; liver damage is also a risk with
long-term use. In vitro studies of human melanocytes exposed to arbutin at concentrations below 300
µg/mL reported decreased tyrosinase activity and melanin content with little evidence of cytotoxicity.
Arbutin did not induce mutations in hamster V79 cells, except after preincubation with β-glycosidase.
Bone marrow micronuclei were not induced in mice after oral treatment with arbutin, and a mixture of
uva ursi extracts did not induce micronuclei in cultured human lymphocytes.
i
Executive Summary
Basis for Nomination
Arbutin is a natural product found in foods, over-the-counter drugs, herbal dietary supplements, or via
dermal contact from and cosmetic skin-lightening products. Arbutin was nominated by the National
Institute for Environmental Health Sciences (NIEHS) for in vitro and in vivo metabolism and disposition
and genotoxicity studies. The nomination is based on widespread human exposure, insufficient
toxicological data, and suspicion of toxicity due to hydrolysis to hydroquinone (HQ). Further studies are
needed to clarify rodent and human differences in biological disposition of arbutin and conversion to HQ.
Previous National Toxicology Program (NTP) studies demonstrated that HQ induced renal tubule
adenomas in male rats and liver adenomas and thyroid gland follicular cell hyperplasia in mice.
Nontoxicological Data
General Information: Arctostaphylos uva ursi (also called Arctostaphylos, bearberry, and beargrape) is
an evergreen perennial shrub flourishing in humus-rich soil of North America, Europe, and Asia. The
leaves are used in medicinal products to treat urinary tract infection, cystitis, and kidney stones. The
active compound in uva ursi, arbutin, is converted to HQ, which has antimicrobial, astringent, and
disinfectant properties. In several plant species (e.g., Arctostaphylos and Calluna), quince jam samples,
and commercial cream samples, arbutin can be quantitatively determined by high performance liquid
chromatography. Uva ursi is commercially available as crushed leaf or powder, and arbutin is available
in both natural and synthetic forms. Arbutin can be synthesized from acetobromglucose and HQ or from
the reaction of β-D-glucose pentaacetate and HQ monobenzyl ether in the presence of phosphorus
oxychloride. It can be formed in vitro by the incubation of HQ with enzyme extracts from bean or wheat
plants or from the germination of seeds or plant tissues in the presence of HQ. Arbutin is used as a
stabilizer for color photographic images and as an anti-infective for the urinary system as well as a
diuretic. It is also an inhibitor of melanin formation and a skin-lightening agent. In the United States,
uva ursi leaf is used as a urinary antiseptic and diuretic in numerous dietary supplements.
Environmental Occurrence and Persistence: In the leaves of A. uva-ursi, the arbutin content generally
ranges from 5.95 to 7.16%. In a study of wild populations of A. uva-ursi in various regions of Spain,
arbutin levels were found to be significantly higher in autumn than in spring. The concentrations also
varied based on plant location. Arbutin was a chemical constituent in the aqueous leachate from foliar
branches and leaf litter of A. glandulosa var. zacaensis, which was toxic to the growth of annual grasses.
Human Exposure: Potential human exposure to arbutin can occur via ingestion, inhalation, or dermal
contact. Arbutin-containing foods include marjoram, pears, Japanese pepper, potatoes infected with
fungi, honeys in Italy and Sardinia, and beverages. Uva ursi is generally used as crushed leaf or powder,
an infusion or cold macerations, and fluidextract, providing 400-840 mg arbutin per day. As the dry
extract, 100-210 mg arbutin is supplied to the individual. It is also available as a capsule, tea, and
tincture. Exposure can also occur through the use of herbal mixtures that contain bearberry or uva ursi.
In the 1981-1983 National Institute for Occupational Safety and Health (NIOSH) National Occupational
Exposure Survey (NOES), an estimated 2629 workers (595 of which were females) were potentially
exposed to uva ursi in the Chemicals and Allied Products industry.
Regulations: Bearberry is not generally recognized as safe and effective. In October 1990, the Food and
Drug Administrations (FDA) proposed to ban the use of 111 ingredients, including bearberry, in
nonprescription diet drug products. When the ban became effective, uva ursi-potassium extract was
specifically named. Bearberry (extract of uva ursi) and bearberry fluidextract (extract of bearberry) were
included among ingredients in a proposed ban on the use of nonprescription orally administered menstrual
drug products. Under §111.100(d), the FDA proposed requiring that no ingredient with a known
ii
stimulant effect, such as uva ursi, be combined in a dietary supplement containing ephedrine alkaloids.
As OTC drug products, the use of bearberry and "uva ursi, potassium extract" as anorectics for weight
control is regulated under 21 CFR 310.545(a)(20) and the use of bearberry (extract of uva ursi) and
bearberry fluidextract (extract of bearberry) as a "menstrual/diuretic" is regulated under 21 CFR
310.545(a)(24).
Toxicological Data
No short-term/subchronic or chronic exposure, carcinogenicity, initiation/promotion, or anti- or cogenotoxicity studies were available.
Human Data: Possible side effects of uva ursi administration are nausea, vomiting, irritability, insomnia,
and an increased heart rate. Extremely high doses of uva ursi (i.e., ten times the recommended amount)
can cause ringing in the ears, shortness of breath, convulsions, collapse, delirium, and vomiting. Uva ursi
has also been linked with albuminuria, hematuria, and urine cast.
Arbutin was found to be extensively absorbed from the gastrointestinal tract and bioavailable as HQ.
Volunteers consuming a meal consisting of high levels of arbutin- and HQ-containing foods had
significant increases in mean total HQ plasma levels. Urinary total HQ excretion rates were also
significantly increased. Four hours after ingestion of a single dose of a preparation containing bearberry
leaf extract (945 mg corresponding to 210 mg arbutin), 224.5 µmol/L HQ glucuronide and 182 µmol/L
HQ sulfate were recovered in the urine, which represented approximately half the administered arbutin
dose. In an open, randomized, two-way crossover study, 16 healthy volunteers received a single oral dose
of bearberry leaves dry extract (BLDE) as film-coated tablets (472.5 mg BLDE, corresponding to 105 mg
arbutin) or as an aqueous solution (945 mg BLDE, corresponding to 210 mg arbutin). HQ glucuronide
and HQ sulfate were recovered in the urine during the first four hours. The total metabolite concentration
represented 66.7% of the administered dose in the tablets and 64.8% in the solution; HQ glucuronide
accounted for 67.3% and 70.3% of the total arbutin metabolites recovered in each group, respectively.
Absorption, Distribution, Metabolism, and Excretion: Because arbutin is reported to hydrolyze easily in
dilute acids to yield D-glucose and HQ, it is expected that ingested arbutin would be hydrolyzed to free
HQ by stomach acids.
In female Wistar rats given an aqueous solution of chromatographically pure arbutin, unchanged arbutin
was excreted at 82% and 100% after 16 and 30 hours post-treatment, respectively, corresponding to
90.7% of the total arbutin dose administered orally. Oral administration of arbutin (500 mg/kg) to female
rats which were overloaded with fluid resulted in a four-fold excess of excreted urine during the second
hour of dosing and a total increase of 61% in the first day. No free HQ was detected in the urine samples.
Arbutin uptake by the jejunum and ileum of rats with a bile fistula and those that received a restricted diet
for five days was increased. The addition of sodium taurocholate to both groups of animals depressed
arbutin uptake in both jenunum and ileum towards normal values. Taurocholate also depressed uptake of
arbutin in the ileum only of normal animals.
Acute Exposure: In mice orally or intraperitoneally (i.p.) treated with arbutin (50-200 mg/kg), a dosedependent antitussive effect to ammonia-induced cough was observed. Arbutin had no analgesic or
anesthetic effects nor any effects on tracheal smooth muscle contraction, respiratory activity, spontaneous
behavior, blood pressure, heart rate or electrical activity. At a dose of 8000 mg/kg administered i.p. for
two weeks, no toxic effects were observed.
Synergistic/Antagonistic Effects: A. uva-ursi extract or arbutin in combination with prednisolone.
indomethacin, or dexamethasone inhibited swelling of contact dermatitis induced by picryl chloride (PCCD) in mice, sheep red blood cell delayed type hypersensitivity (SRBC-DTH) response, and/or
iii
carrageenin-induced paw edema to a greater extent than did any of the chemicals alone. Uva ursi may
also increase the anti-inflammatory effects of nonsteroidal anti-inflammatory drugs, such as ibuprofen
and indomethacin. Aloesin (an anti-inflammatory) and arbutin synergistically inhibit tyrosinase activity.
In a study of their effects on UV-induced pigmentation in human skin in vivo, co-treatment with both
chemicals (100 mg/g each) produced an additive effect. Additionally, arbutin inhibited UV-induced
nuclear factor-kappaB activation in human keratinocytes. An A. uva-ursi extract, considered for use in
food preservation, enhanced the antimicrobial activity of nisin. In mouse skin, arbutin counteracted
oxidative stress induced by 12-O-tetradecanoylphorbol-13-acetate.
Cytotoxicity: Growth of human melanoma cells and normal human melanocytes was not inhibited by
exposure to 100 µg/mL arbutin for five days. At 300 µg/mL arbutin treatment for five days, cell toxicity
and detachment of cells from the dishes were observed within 48 hours.
Reproductive and Teratological Effects: Daily subcutaneous (s.c.) injection of arbutin (25, 100, or 400
mg/kg) into male and female Sprague-Dawley rats before mating and into females during pregnancy and
lactation resulted in a maximum no-effect dose of 100 mg/kg/day for reproduction and for development
and growth of their offspring. Oral administration of arbutin (lowest published toxic dose = 13,600
mg/kg) for 14 days prior to copulation and 20 days of pregnancy produced effects (not specified) in the
ovaries and fallopian tubes. Fetotoxicity but no deaths was reported.
Anticarcinogenicity: Arbutin (2.5, 12.5, or 50 µg/mL) incubated for four days weakly inhibited the
growth of human colon carcinoma HCT-15 cells.
Genotoxicity: Arbutin (up to 0.01 M) did not induce mutations in hamster V79 cells; however, after
preincubation of arbutin (≥1 mM) with β-glycosidase, it did have a mutagenic effect. Arbutin (0.5-2 g/kg
bw) did not induce micronuclei in the bone marrow of mice, while a mixture of extracts of Uva ursi
(0.025, 0.05, 0.1, or 0.2 mg/mL) did not affect the level of micronuclei in cultured human blood
lymphocytes.
Immunotoxicity: In a murine local lymph node assay, arbutin (5, 10, or 20%), applied to Balb/c female
mice after topical treatment with the weak allergen α-hexylcinnamaldehyde, did not produce contact
sensitization. Oral application of arbutin (10 or 50 mg/kg) quickly reduced the swelling of PC-CD and
SRBC-DTH within 24 hours. Arbutin (1 mg/mL) also inhibited the binding of mouse monoclonal antidinitrophenyl immunoglobulin E (IgE[aDNP]) to DNP by 65%. In macrophage cells from male Swiss
mice, arbutin (2 mg/mL) failed to induce the release of hydrogen peroxide.
Other Data: Arbutin added to cultured human melanocytes showed a concentration-dependent reduction
in tyrosinase activity and significantly reduced melanin content with low cytotoxicity. A 50% methanol
extract of A. uva-ursi and arbutin isolated from the bearberry leaf also inhibited tyrosinase activity and
melanin production in vitro. Arbutin exhibited potent inhibitory effects on rat platelet aggregation
induced by adenosine diphosphate and collagen.
In unanaesthetized male and female cats administered oral (p.o.) and i.p. doses of arbutin (50 and 100
mg/kg bw) in water, a statistically significant decrease in the number, intensity, and frequency of coughs
was observed at the lower dose. An increase in antitussive activity was not seen with the higher dose.
Structure-Activity Relationships
Hydroquinone (HQ) [CAS No. 123-31-9]
In a two-year carcinogenesis bioassay, HQ (25 or 50, or 100 mg/kg) administered by gavage gave some
evidence of carcinogenicity in male F344/N rats (kidney tubular cell adenoma), female F344/N rats
(mononuclear cell leukemia), and female B6C3F1 mice (liver adenoma or carcinoma). Additionally, the
iv
incidence of thyroid follicular cell hyperplasia was increased in female and male mice. In Salmonella
typhimurium strains TA98, TA100, TA1535, and TA1537, HQ was negative for mutagenicity in the
presence and absence of metabolic activation (S9). In Chinese hamster ovary (CHO) cells, it induced
sister chromatid exchanges (with and without S9) and chromosomal aberrations (with S9). HQ also
induced trifluorothymidine resistance in mouse L5178Y/TK lymphoma cells and was mutagenic in the
micronucleus test. Inconclusive results, however, were obtained in Drosophila.
Hydroquinone Monomethyl Ether [CAS No. 150-76-5]
HQ monomethyl ether was negative in Salmonella mutagenicity assays.
tert-Butylhydroquinone (TBHQ) [CAS No. 1948-33-0]
TBHQ (0.125, 0.25, or 0.5% [1250, 2500, or 5000 ppm]) administered in feed for two years (mice) or
lifetime (rats) produced no evidence of carcinogenicity in male and female Fischer 344 rats and B6C3F1
mice. When the rats were placed on a diet restriction (0 or 5000 ppm in feed for 30 months), survival
rates increased, while the incidences of neoplasms and nonneoplastic lesions at various sites were
maintained. In S. typhimurium strains TA97, TA98, TA100, and TA102, negative results were obtained
with and without S9. TBHQ was also not mutagenic in the micronucleus test. In CHO cells, it induced
sister chromatid exchanges and chromosome aberrations in the presence of S9 only. In immunotoxicity
tests, TBHQ (25, 75, or 150 mg/kg) administered via gavage to B6C3F1 mice produced increases in the
amount of the third component of serum complement, Fc-mediated adherence and phagocytosis by
peritoneal adherent cells, natural killer cell activity, liver and spleen weights, reticulocyte number, and
blood glucose and a decrease in the number of neutrophils.
v
Table of Contents
Abstract........................................................................................................................................... i
Executive Summary ...................................................................................................................... ii
1.0
Basis for Nomination .........................................................................................................1
2.0
Introduction........................................................................................................................1
2.1
Chemical Identification and Analysis ..................................................................2
2.2
Physical-Chemical Properties ...............................................................................2
2.3
Commercial Availability .......................................................................................3
3.0
Production Processes .........................................................................................................3
4.0
Production and Import Volumes......................................................................................3
5.0
Uses......................................................................................................................................3
6.0
Environmental Occurrence and Persistence ...................................................................4
7.0
Human Exposure ...............................................................................................................4
8.0
Regulatory Status...............................................................................................................4
9.0
Toxicological Data..............................................................................................................5
9.1
General Toxicology ................................................................................................5
9.1.1 Human Data ...............................................................................................5
9.1.2 Chemical Disposition, Metabolism, and Toxicokinetics.........................6
9.1.3 Acute Exposure ..........................................................................................8
9.1.4 Short-term and Subchronic Exposure .....................................................8
9.1.5 Chronic Exposure ......................................................................................8
9.1.6 Synergistic/Antagonistic Effects ...............................................................8
9.1.7 Cytotoxicity.................................................................................................9
9.2
Reproductive and Teratological Effects...............................................................9
9.3
Carcinogenicity ......................................................................................................9
9.4
Initiation/Promotion Studies.................................................................................9
9.5
Anticarcinogenicity ................................................................................................9
9.6
Genotoxicity............................................................................................................9
9.7
Cogenotoxicity ......................................................................................................10
9.8
Antigenotoxicity ...................................................................................................10
9.9
Immunotoxicity ....................................................................................................10
9.10 Other Data ............................................................................................................10
10.0 Structure-Activity Relationships ....................................................................................10
11.0 Online Databases and Secondary References................................................................12
11.1 Online Databases..................................................................................................12
11.2 Secondary References..........................................................................................12
12.0 References.........................................................................................................................13
13.0 References Considered But Not Cited............................................................................21
Acknowledgements ......................................................................................................................22
Appendix A: Units and Abbreviations......................................................................................23
Appendix B: Description of Search Strategy and Results.......................................................24
vi
Chemical Information Review Document for Arbutin [497-76-7] and Extracts from Arctostaphylos uva-ursi
01/2006
1.0
Basis for Nomination
Arbutin is a natural product found in foods, over-the-counter drugs, herbal dietary supplements,
and cosmetic skin-lightening products. Arbutin was nominated by the National Institute for
Environmental Health Sciences (NIEHS) for in vitro and in vivo metabolism and disposition and
genotoxicity studies. The nomination is based on widespread human exposure, insufficient
toxicological data, and suspicion of toxicity due to hydrolysis to hydroquinone (HQ). Further
studies are needed to clarify rodent and human differences in biological disposition of arbutin
and conversion to HQ. Previous National Toxicology Program (NTP) studies demonstrated that
HQ induced renal tubule adenomas in male rats and liver adenomas and thyroid gland follicular
cell hyperplasia in mice.
2.0
Introduction
Arbutin
[497-76-7]
Arbutin is found in the dried leaves of bearberry (Arctostaphylos uva-ursi Spreng., Ericaceae),
blueberry, cranberry, and pear trees (Pyrus communis L., Rosaceae); cowberry (Vaccinium vitisidaea L., Ericaceae), Bergenia crassifolia (L.) Fritsch, and Saxifragaceae. It is generally present
in plants in combination with methylarbutin, especially plants of the Ericaceae family (Budavari,
1996). Arbutin has also been isolated in numerous other plant sources, such as in juvenile
foliage of the New Zealand tree Halocarpus biformis, Salvia mexicana L. var. minor Benth,
Rhodiola sacra S H Fu, Onobrychis viciifolia (Sainfoin), and Origanum majorana (Assaf et al.,
1987; Delira et al., 2003; Fan et al., 1999; Marais et al., 2000; Perry et al., 1996).
Arctostaphylos uva ursi is an evergreen perennial shrub flourishing in humus-rich soil of North
America, Europe, and Asia. Uva ursi contains HQ derivatives (mostly arbutin), polyphenolic
tannins, free-form phenolic acids, flavonoids, triterpenes, monotropein, resin, volatile oil, and
wax. Commercially available materials derived from uva ursi come entirely from wild plants
collected throughout Europe, primarily Spain, Italy, the Balkans, and the USSR. The leaves are
used in medicinal products, mainly to treat urinary tract infection, cystitis, and kidney stones.
The active compound in uva ursi, arbutin, is converted to HQ, which has antimicrobial,
astringent, and disinfectant properties (Am. Botanical Council, 2000; A.D.A.M., Inc., 2004).
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Chemical Information Review Document for Arbutin [497-76-7] and Extracts from Arctostaphylos uva-ursi
01/2006
2.1
Chemical Identification and Analysis
Arbutin (C12H16O7; mol. wt. = 272.25) is also called:
β-Arbutin
Arbutine
Arbutoside
β-D-Glucopyranoside 4-hydroxyphenyl- (9CI)
Glucopyranoside, p-hydroxyphenyl, β-D- (6CI, 7CI)
Hydroquinone-β-D-glucopyranoside
Hydroquinone glucose
4-Hydroxyphenyl-β-D-glucopyranoside
NSC 4036
Ursin
Uvasol
Sources: Budavari (1996); Registry (1984); RTECS (1997)
In several species (e.g., Arctostaphylos and Calluna), arbutin can be quantitatively determined by
high performance liquid chromatography (HPLC) (Parejo et al., 2002; Sticher et al., 1979; Sun et
al., 1997). Thin-layer chromatography (TLC) can be used for qualitative analysis (Rychlinska
and Gudej, 2003). The main urinary metabolites of arbutin, HQ, HQ glucuronide and HQ
sulfate, have been analyzed in human urine by capillary electrophoresis (CE), HPLC, and HPLC
with coulometric-array detection (Glockl et al., 2001; Siegers et al., 2003; Süβ et al., 2000 abstr.;
Wittig et al., 2001).
Arbutin content in quince jam samples was analyzed by reversed-phase HPLC with a diode array
detector, suggesting the jams may be adulterated with pear puree (Silva et al., 2000, 2001).
Commercial arbutin cream samples were analyzed using reversed-phase HPLC with photodiode
array detection. The recover range was 98.2-102.2% and the quantitation limit was 15 µg/mL.
A storage-stability study was performed on commercial arbutin cream and spiked cream samples
stored in 0.05 M KH2PO4 buffer (pH 2.5). Arbutin was stable in all samples up to four days of
storage. The spiked cream and commercial cream began to hydrolyze after eight days. Arbutin
recovery was 73.4% after one month of storage (Huang et al., 2004).
2.2
Physical-Chemical Properties
Property
Physical State
Boiling Point (oC)
Melting Point (oC)
Flash Point (oC)
Vapor Pressure (Torr)
Soluble in:
Molar Solubility
Bioconcentration Factor
Adsorption Coefficient (KOC)
Octanol-water partition
coefficient (log P)
Information
Needles (from hot ethyl acetate)
561.6±50.0 @ 760 Torr
165 (unstable form), 199.5-200
(stable form)
293.4±54.2
1.90x10-13 @ 25 °C
alcohol and water
≥0.1 - <1 M @ pH 1-10
1 @ pH 1-10
3.67 @ pH 1-10
-1.494±0.197
Reference(s)
Budavari (1996)
Registry (1984)*
Budavari (1996)
Registry (1984)*
Registry (1984)
Budavari (1996)
Registry (1984)*
Registry (1984)*
Registry (1984)*
Registry (1984)*
*calculated using Advanced Chemistry Development (ACD/Labs) Software Solaris V4.67(©1994-2004 ACD/Labs)
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Chemical Information Review Document for Arbutin [497-76-7] and Extracts from Arctostaphylos uva-ursi
01/2006
Arbutin is very hygroscopic. It is readily hydrolyzed by dilute acids or emulsin, producing
D-glucose and HQ in a 1:1 mole ratio (Budavari, 1996).
2.3
Commercial Availability
Arbutin is available commercially in both natural and synthetic (hydroquinone-β,Dglucopyranoside) forms (Lewis, 1993). ChemNet.com, a registered trademark of Hangzhou
Hi2000 InfoTech Co. Ltd. lists several suppliers of Arbutin in 2-2000 kg quantities. Some
websites, including amazon.com, list retail and wholesale suppliers (e.g., Nature's Way, Herb
Pharm, Nature’s Herbs, Planetary Formulations, Solaray, Nature’s Answer, Eclectic Institute).
Arbutin assayed at 99% is available from 01Wholesale.com. Uva ursi is commercially available
as crushed leaf or powder. The material comes entirely from wild plants collected throughout
Europe, primarily Spain, Italy, the Balkans, and the former USSR (Am. Botanical Council, 2000;
A.D.A.M., Inc., 2004). American Nutrition Center supplies uva ursi (Bearberry) 4:1, uva ursi
bearberry with 20% arbutin, and uva ursi leaf standard with 10% arbutin. Internet searches also
found bulk raw material ingredients are supplied by Organic Herbs Inc. and Peakchem in China
and Richman Chemicals in the U.S.A.
3.0
Production Processes
Arbutin can be synthesized from acetobromglucose and HQ or from the reaction of β-D-glucose
pentaacetate and HQ monobenzyl ether in the presence of phosphorus oxychloride (Budavari,
1996). It can be formed in vitro by the incubation of HQ with enzyme extracts from bean or
wheat plants or from the germination of seeds (e.g., Viguna mungo seeds) or plant tissues in the
presence of HQ (Deisinger et al., 1996; Fujiwara and Suzuki, 1995 pat. appl.). Arbutin is also
produced by biotransformation of HQ by Catharanthus roseus cells (Misawa, 1994).
4.0
Production and Import Volumes
No data were available.
5.0
Uses
Arbutin is used as a stabilizer for color photographic images. Therapeutically, it is used as an
anti-infective for the urinary system as well as a diuretic (Budavari, 1996). It is also an inhibitor
of melanin formation and a skin-lightening agent that is included in compositions used for
treating skin cancer (Fujiwara and Suzuki, 1995 pat. appl.; Patrice, 1998 pat.). In a pilot study of
healthy adults exposed to ultraviolet (UV) B radiation followed by topical treatment with arbutin,
hyperpigmentation was inhibited in 4/6 volunteers (Kemper et al., 1999; Kim et al., 1994). In a
more recent study, UV-induced pigmentation in the skin (forearm) of 15 Korean men (23-27
years old) was suppressed 43.5% by arbutin (100 mg/g [0.367 mmol/g]) (Choi et al., 2002).
In the United States, uva ursi leaf is used as a urinary antiseptic and diuretic in numerous dietary
supplements (Am. Botanical Council, 2000). As over-the-counter (OTC) drugs, bearberry and
"uva ursi, extract" are used as anorectics for weight control, and bearberry (extract of uva ursi)
and bearberry fluidextract (extract of bearberry) are used as a "menstrual/diuretic" (FDA, 2003).
Uva ursi (bearberry, upland cranberry) can be used for acute treatment and prevention of
recurrent cystitis (Bozzuto, 2001). The use of bearberry leaves as a smoking-tobacco substitute
was also mentioned. Native Americans combined the leaves with tobacco; they also powdered
3
Chemical Information Review Document for Arbutin [497-76-7] and Extracts from Arctostaphylos uva-ursi
01/2006
the leaves and applied them to sores. Bearberry can be used to make an astringent wash or as an
endometrial vasoconstrictor (Crane, 1991; Kemper, 1999; Manybeads et al., 2001).
6.0
Environmental Occurrence and Persistence
Arbutin is found in the dried leaves of a variety of plant species (see Section 2.0). In A. uva-ursi,
the arbutin content generally ranges from 5.95 to 7.16%. In a study of wild populations of A.
uva-ursi in various regions of Spain, arbutin levels were found to be significantly higher in
autumn than in spring. The concentrations also varied based on plant location: in spring, the
highest levels were found in plants from Cloterons (8.05% dry weight) and the lowest ones in
those from Adraén Baix (6.30%); in autumn, the concentrations were highest in Adraén Alt
(9.10%) and lowest in Guils de Cerdanya (6.97%). The bearberry density was 80-100% in
Cloterons and Adraén Baix, 60-80% in Adraén Alt, and 15-20% Guils de Cerdanya, (Parejo et
al., 2002).
7.0
Human Exposure
Potential human exposure to arbutin is most likely to occur occur via ingestion or dermal contact.
Arbutin-containing foods include marjoram, pears (fruit, juice, possible adulterant in quince
products), Japanese pepper, potatoes (Solanum tuberosum) infected with fungi, foods of Native
Canadians, honeys in Italy and Sardinia, and beverages (Deisinger et al., 1996; Keller et al.,
1996; Schmidt, 1969 diss.). Significant amounts of arbutin levels were found in wheat products
(1-10 ppm [4-37 µmol/kg]), pears (4-15 ppm [0.01-0.055 mmol/kg]), and coffee and tea (0.1
ppm [0.4 µM]) (Deisinger et al., 1996). Uva ursi is generally taken by adults as crushed leaf or
powder, an infusion or cold macerations, and fluidextract, providing 400-840 mg [1.47-3.09
mmol] arbutin per day. As the dry extract, 100-210 mg [0.367-0.771 µmol] arbutin are supplied
to the individual (Am. Botanical Council, 2000). It is also available as a capsule, tea, and
tincture (A.D.A.M., Inc., 2004). It has been estimated that an individual who drinks up to 3 g of
tea from uva ursi leaves (which contain up to 6% HQ glycosides) four times a day consumes
~720 mg arbutin (2.64 mmol; ~12 mg/kg bw) (Müller and Kasper, 1996 abstr.). Exposure can
also occur through the use of herbal mixtures that contain bearberry or uva ursi (see Section 5.0).
In the 1981-1983 National Institute for Occupational Safety and Health (NIOSH) National
Occupational Exposure Survey (NOES), an estimated 2629 workers (595 of which were females)
were potentially exposed to uva ursi in the Chemicals and Allied Products industry (Standard
Industrial Classification [SIC] 28). Workers in the packaging area had the highest potential
exposure. In a separate survey, which is apparently a subset of the uva ursi data, the total
number of employees exposed to uva ursi powdered extract was approximated at 1339; this was
also in SIC 28 (NIOSH, undated).
8.0
Regulatory Status
Bearberry is not generally recognized as safe and effective. In October 1990, the Food and Drug
Administration (FDA) proposed to ban the use of 111 ingredients, including bearberry, in
nonprescription diet drug products (FDA, 1990 press release). When the ban became effective,
uva ursi-potassium extract was specifically named (FDA, 1991 press release). Bearberry (extract
of uva ursi) and bearberry fluidextract (extract of bearberry) were included among ingredients in
a proposed ban on the use of nonprescription orally administered menstrual drug products (FDA,
1992 press release). In 1999, the OTC drug e-Ludesô Capsules, containing uva ursi, was
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recalled due to its being marketed without an approved new drug application (FDA, 1999).
Under §111.100(d), the FDA proposed requiring that no ingredient with a known stimulant
effect, such as uva ursi, be combined in a dietary supplement containing ephedrine alkaloids
(FDA, 2000b). In 2000, dietary supplements manufactured by Hillestad Pharmaceuticals
(Woodruff, WI) containing uva ursi and other ingredients such as saw palmetto were seized due
to their status as unapproved new drugs and their failure to display adequate directions for use
(FDA, 2000a). In the OTC Ingredient List, the use of bearberry and uva ursi, potassium extract
as anorectics for weight control is regulated under 21 CFR 310.545(a)(20) and the use of
bearberry (extract of uva ursi) and bearberry fluidextract (extract of bearberry) as a
"menstrual/diuretic" is regulated under 21 CFR 310.545(a)(24); marketing of these products for
these uses requires an approved new drug application (FDA, 2003). A. uva-ursi is an
unapproved herbal product currently marketed for use in animals as a diuretic and urinary
antiseptic (FDA CVM, 2000).
9.0
Toxicological Data
Note: Several toxicity studies in the following sections were published in their original nonEnglish languages. These are noted in the citations in brackets. When available, translated
abstracts were used. Therefore, full details were not provided in most cases.
9.1
General Toxicology
9.1.1 Human Data
In persons with sensitive stomachs, nausea and vomiting are possible side effects from the
ingestion of dried uva ursi leaves (as low as 15 g [0.055 mol]); other symptoms that have been
reported are irritability, insomnia, and an increased heart rate (Am. Botanical Council, 2000;
A.D.A.M., Inc., 2004). Extremely high doses of uva ursi (i.e., ten times the recommended
amount) can cause ringing in the ears, shortness of breath, convulsions, collapse, delirium, and
vomiting. Liver damage is a risk with long-term use (Murray, 1997; Whole Foods Market,
2003).
A 78-year-old woman, experiencing recurrent edematous pruritic erythema on the periorbital
areas and cheeks over a nine-month period, patch-tested positive for arbutin which was found in
one of the cosmetics she had been using for two years (Sugawara et al., 2002).
Uva ursi use has also been linked to albuminuria, hematuria, and urine cast (Adesunloye, 2003).
Uva ursi extract, used in a treatment study of 57 women with recurrent cystitis, produced no side
effects. At the end of one year of treatment, 5/27 women in the placebo group had a recurrence
compared to 0/30 women in the treatment group. Neither group reported side effects (Larsson et
al., 1993 [cited by Kemper, 1999 and Murray, 1997]).
Several case reports exist where herbal supplements or mixtures containing uva ursi have been
implicated as the cause. In a 56-year-old female who drank tea containing uva ursi regularly for
three years to prevent recurrent urinary tract infection, bull's eye maculopathy, paracentral
scotomas, reduction in electroretinography amplitude, and retinal thinning on optical coherence
tomography were observed. The maculopathy was suspected to result from uva ursi because of
its ability to inhibit melanin synthesis (Wang and Del Priore, 2004). In another case report, a 52year-old woman who ingested the herbal remedy CKLS (a colon, kidney, liver, and spleen
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purifier), which includes uva ursi among its ingredients, developed acute renal failure; however,
aloe vera and cascara sagrada also present in the remedy were more likely the contributory
factors (Adesunloye, 2003).
Absorption, Distribution, Metabolism, and Excretion: Arbutin was found to be extensively
absorbed from the gastrointestinal (GI) tract and bioavailable as HQ. Volunteers (two males and
two females, 36-45 years old) consuming a meal consisting of high levels of arbutin- and HQcontaining foods (coffee or tea, wheat cereal, whole wheat bread, wheat germ, and Bosc pears)
had significant increases in mean total HQ (i.e., HQ and its conjugated metabolites) plasma
levels; after two hours, it was five times the background concentration (at 0.15 µg/g [0.55
nmol/g]). Urinary total HQ excretion rates were also significantly increased; after two-three
hours, levels were 12 times background levels. A low-HQ diet (corn cereal, 2% milk,
cantaloupe, black cherry yogurt, and soft drink) resulted in a slight decrease in the mean levels of
HQ in human plasma and urine (Deisinger et al., 1996).
Four hours after ingestion of a single dose of a preparation containing bearberry leaf extract (945
mg corresponding to 210 mg [0.771 mmol] arbutin), 224.5 µmol/L HQ glucuronide and 182
µmol/L HQ sulfate were recovered in the urine, which represented approximately half the
administered arbutin dose (Glockl et al., 2001). In an open, randomized, two-way crossover
study, 16 healthy volunteers (8 males, 8 females, mean age of 25.4-years-old) received a single
oral dose of bearberry leaves dry extract (BLDE) as film-coated tablets (472.5 mg BLDE,
corresponding to 105 mg [0.386 mmol] arbutin) or as an aqueous solution (945 mg BLDE,
corresponding to 210 mg [0.771 mmol] arbutin). HQ glucuronide and HQ sulfate were
recovered in the urine during the first four hours but no metabolites were detected after 24 hours.
The rate of metabolism was faster in the group given BLDE in an aqueous solution. The total
metabolite concentration represented 66.7% of the administered dose in the tablets and 64.8% in
the solution. HQ glucuronide accounted for 67.3% and 70.3% of the total arbutin metabolites
recovered in each group, respectively (Schindler et al., 2002).
Urine samples collected at four-hour intervals from volunteers who were kept on a xanthine- and
arbutin-free diet and given bearberry leaf extract were used to develop an HPLC and
coulometric-array detection method for measuring HQ in human urine. Specificity and
selectivity were carried out by separation experiments involving the prodrug arbutin and its
metabolites (Wittig et al., 2001). Urine samples collected from four volunteers given 6 dragees
Cystinol akut (an antiseptic; 420 mg [1.54 mmol] arbutin, equivalent to 168 mg HQ) were
assayed with or without added glusulase or an E. coli suspension, and analyzed by HPLC for
HQ. Free HQ from the conjugation of HQ glucuronide and sulfate was 2.3-fold higher in the E.
coli-suspension compared to the glusulase incubate. The HQ concentration in bacteria following
separation from the urine was 20-fold higher than that in the supernatant (Siegers et al., 2003).
9.1.2 Chemical Disposition, Metabolism, and Toxicokinetics
Because arbutin is reported to hydrolyze easily in dilute acids to yield D-glucose and HQ, it is
expected that ingested arbutin would be hydrolyzed to free HQ by stomach acids (Deisinger et
al., 1996).
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Female Wistar rats were given an aqueous solution of chromatographically pure arbutin, isolated
from Arctostaphylos uva-ursi, and their excreted urine was evaluated by TLC, HPLC and
spectral analysis. Unchanged arbutin was excreted at 82% and 100% after 16 and 30 hours posttreatment, respectively, corresponding to 90.7% of the total arbutin dose administered orally
(Johdodar et al., 1983).
Oral administration of arbutin (500 mg/kg [1.84 mmol/kg]) to female rats which were overloaded
with fluid resulted in a fourfold excess of excreted urine during the second hour of dosing and a
total increase of 61% in the first day. No free HQ was detected in the urine samples. Diuretic
activity from treatment with 200 mg/kg HQ was greater than that observed in arbutin-treated
animals (Temple et al., 1971).
The relationship of bile salts to intestinal sugar transport was investigated in vitro and in vivo in
adult Wistar rats. The rate of sugar uptake (with 5 mM [1 mg/mL] arbutin as substrate) in vitro
was severely impaired by bile salts throughout the incubation period, persisting for 72 hours; the
rate of absorption of arbutin in vivo was significantly depressed by bile salts for 48 hours and
returned to normal after 72 hours (Gracey et al., 1973).
Arbutin uptake by the jejunum and ileum of rats with a bile fistula and those that received a
restricted diet for five days was increased. The addition of sodium taurocholate to both groups
of animals depressed arbutin uptake in both jenunum and ileum towards normal values.
Taurocholate also depressed uptake of arbutin in the ileum only of normal animals. Since the
results in the bile fistula rats (which only consumed approximately one-third as much food as
normal rats over the first five days) and rats on a restricted diet were similar, the authors
suggested monosaccharide uptake was related to reduced food intake and not the effect of bile
salts (Burke et al., 1978).
The effect of microorganisms isolated from the upper GI tract of malnourished Indonesian
patients (10 boys and 10 girls, 1 month to 4 years of age) on intestinal sugar transport was also
studied in rats in vivo. Specimens of intestinal contents were obtained by pernasal intubation of
the duodenum after four hours of fasting, cultured in selective media, and grown overnight in a
nutrient broth. The resulting supernatant containing microorganisms in similar numbers to those
found in the patients was used for the perfusion experiment in anesthetized Wistar rats. Grampositive cocci (Staphylococcus saprophyticus) and the Enterobacteriaciae organisms (Salmonella
paratyphi B, a Shigella and Proteus species) did not adversely affect intestinal absorption of
arbutin (10 mM [2.7 mg/mL]); however, the gram-positive rod, Lactobacillus and all the species
of E. coli inhibited arbutin absorption.
Many organisms not generally considered
enteropathogenic inhibited intestinal absorption when present in the lumen of the GI tract
(Gracey et al., 1975).
Albino Wistar rats (normal and protein-deprived) were fed Candida albicans (1x109
organisms/mL) by intragastric inoculation for three days. In an in vivo absorption study, arbutin
uptake was decreased in both groups of animals. Specimens from the small intestine were also
incubated for 30 minutes with Krebs Henseleit (KH) buffer containing 3 mM arbutin and 2 mM
2-deoxy-glucose. Arbutin uptake in vitro decreased throughout the incubation period for
samples from both normal and protein-deprived animals (Burke and Gracey, 1980).
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A method for screening glycosides such as arbutin, which delayed the time-course effect of sugar
absorption in mice, was reported. Male Std ddY mice were given a glucose solution with or
without phlorizin or various glycosides via a stomach sonde. Arbutin delayed the postprandial
blood glucose rise following glucose ingestion suggesting it may be a useful additive in treating
diabetic subjects (Takii et al., 1997).
9.1.3 Acute Exposure
In mice orally or intraperitoneally (i.p.) treated with arbutin (50-200 mg/kg [0.18-0.735
mmol/kg]), a dose-dependent antitussive effect to ammonia-induced cough was observed. The
antitussive effect of arbutin (200 mg/kg [0.735 mmol/kg]) was as potent as that of codeine
phosphate (30 mg/kg), but arbutin had no analgesic or anesthetic effects. Additionally, arbutin
had no effect on tracheal smooth muscle contraction, respiratory activity, spontaneous behavior,
blood pressure, heart rate or electrical activity. At a dose of 8000 mg/kg [29.38 mmol//kg]
administered i.p. for two weeks, no toxic effects were observed (Li et al., 1982 [Chin.]).
9.1.4 Short-term and Subchronic Exposure
No data were available.
9.1.5 Chronic Exposure
No data were available.
9.1.6 Synergistic/Antagonistic Effects
Arbutin and A. uva-ursi extract increased the inhibitory potency of prednisolone against swelling
due to contact dermatitis in mice (Kubo et al., 1990 [Jpn.]). In mice, A. uva-ursi extract or
arbutin in combination with prednisolone or dexamethasone inhibited swelling of contact
dermatitis induced by picryl chloride (PC-CD) and sheep red blood cell delayed type
hypersensitivity (SRBC-DTH) response to a greater extent than either of the two chemicals alone
(Kubo et al., 1990 [Jpn.]; Matsuda et al., 1990 [Jpn.]). Water extracts from the leaf of A. uva
ursi also increased the inhibitory effect of dexamethasone ointment on PC-CD- and carrageenininduced paw edema (Matsuda et al., 1992b [Jpn.]). Arbutin plus indomethacin produced the
same results in these models and showed a stronger inhibitory effect than indomethacin alone in
carrageenin-induced edema and adjuvant-induced arthritis (Matsuda et al., 1991 [Jpn.]). Uva
ursi may also increase the anti-inflammatory effects of nonsteroidal anti-inflammatory drugs
(e.g., ibuprofen and indomethacin) (A.D.A.M., Inc., 2004).
Aloesin (an anti-inflammatory) and arbutin synergistically inhibit tyrosinase activity. In a study
of their effects on UV-induced pigmentation in human skin in vivo, co-treatment with both
chemicals (100 mg/g each) produced an additive effect; 63.3% suppression of pigmentation
versus 34% with aloesin and 43.5% with arbutin alone (Choi et al., 2002). Additionally, arbutin
inhibited UV-induced nuclear factor-kappaB activation in human keratinocytes (Ahn et al.,
2003).
An A. uva-ursi extract, considered for use in food preservation, enhanced the antimicrobial
activity of nisin; bearberry extract alone had no effect (Dykes et al., 2003). Arbutin counteracted
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oxidative stress induced by 12-O-tetradecanoylphorbol-13-acetate in mouse skin (Nakamura et
al., 2000).
9.1.7 Cytotoxicity
Growth of human melanoma cells and normal human melanocytes was not inhibited by exposure
to 100 µg/mL [0.367 mM] arbutin for five days. At 300 µg/mL [1.10 mM] arbutin treatment for
five days, cell toxicity and detachment of cells from the dishes were observed within 48 hours
(Chakraborty et al., 1998).
Arbutin (5-50 µM [1-14 µg/mL]) inhibited the growth of the roots of Allium sativum L. and
produced anti-mitotic effects. At 10 µM, the anti-mitotic effect was already visible within 24
hours and ended at 48 hours. At 20 µM [5.4 µg/mL], arbutin was very toxic, completely
stopping root growth after day 1. The effects were similar to those seen with HQ at 5 µM
(Deysson and Truhaut, 1957).
9.2
Reproductive and Teratological Effects
Only one reproductive toxicity study was found [Japanese]. Daily subcutaneous (s.c.) injection
of arbutin (25, 100, or 400 mg/kg [0.092, 0.367, or 1.47 mmol/kg]) to male and female SpragueDawley rats before mating and to females during pregnancy and lactation resulted in a maximum
no-effect dose of 100 mg/kg/day for reproduction and for development and growth of their
offspring. No specifics were provided in the abstract; however, the following parameters were
measured: viability, fertility, and mortality; musculoskeletal system growth; sex ratio; behavior
and psychologic processes; mutigenerational study; reproductive toxicity; and maternal weight
changes (Itabashi et al., 1988). The RTECS (1997) record states the following regarding the
Itabashi et al. (1988) study: Oral (route of administration appears to be incorrectly annotated in
RTECS record) administration of arbutin (lowest published toxic dose = 13,600 mg/kg [49.954
mmol/kg]) for 14 days prior to copulation and 20 days of pregnancy produced maternal effects
(not specified) in the ovaries and fallopian tubes. Fetotoxicity (e.g., stunted fetus) but no deaths
was reported.
9.3
Carcinogenicity
No data were available.
9.4
Initiation/Promotion Studies
No data were available.
9.5
Anticarcinogenicity
Arbutin (2.5, 12.5, or 50 µg/mL [9.2, 45.9, 180 µM]) incubated for four days weakly inhibited
the growth of human colon carcinoma HCT-15 cells (Kamei et al., 1998).
9.6
Genotoxicity
Arbutin (up to 0.01 M [2.73 mg/mL]) did not induce mutations in hamster V79 cells; however,
after preincubation of arbutin (≥1 mM [0.3 mg/mL]) with β-glycosidase, it did have a mutagenic
effect. In mice orally treated with arbutin (0.5-2 g/kg [2-7 mmol/kg] bw), there was no induction
of bone marrow micronuclei (Müller and Kasper, 1996 abstr.).
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A mixture of extracts of Uva ursi (0.025, 0.05, 0.1, or 0.2 mg/mL [0.092, 0.2, 0.4, or 0.7 mM])
did not affect the level of micronuclei in cultured human blood lymphocytes (Joksic et al., 2003).
9.7
Cogenotoxicity
No data were available.
9.8
Antigenotoxicity
No data were available.
9.9
Immunotoxicity
In a murine local lymph node assay (LLNA), arbutin (5, 10, or 20%), applied to Balb/c female
mice after topical treatment with the weak allergen α-hexylcinnamaldehyde, did not produce
contact sensitization (Lee et al., 2003 [Korean]). Oral application of arbutin (10 or 50 mg/kg
[0.037 or 0.18 mmol/kg]) quickly reduced the swelling of PC-CD and SRBC-DTH within 24
hours (Matsuda et al., 1990, 1991 [Jpn.]). (See also Section 9.1.6.) Arbutin (1 mg/mL [4 mM])
inhibited the binding of mouse monoclonal anti-dinitrophenyl immunoglobulin E (IgE[aDNP]) to
DNP by 65% (Varga et al., 1991). In macrophage cells from male Swiss mice, arbutin (2 mg/mL
7 mM]) failed to induce the release hydrogen peroxide (Moreira et al., 2001).
9.10 Other Data
Arbutin added to cultured human melanocytes showed a concentration-dependent reduction in
tyrosinase activity and significantly reduced melanin content with low cytotoxicity (Ding et al.,
2001; Maeda and Fukuda, 1991, 1996; Maeda and Naganuma, 1996; Miyazaki et al., 1998;
Nishimura et al., 1995). The effects on melanocyte pigmentation at an arbutin concentration of
0.5-8 mM were evaluated by a cell-blotting assay. Cells treated with arbutin increased the
pigmentation and decreased the tyrosinase activity of these cells. No changes were detected in
the expression of the tyrosinase gene in melanocytes treated with arbutin (Nakajima et al., 1998).
A 50% methanol extract of A. uva-ursi and arbutin isolated from the bearberry leaf also inhibited
tyrosinase activity and melanin production in vitro (Matsuda et al., 1992a [Jpn.]).
Arbutin exhibited potent inhibitory effects on rat platelet aggregation induced by adenosine
diphosphate (ADP; IC50=0.12 mM) and collagen (IC50=0.039 mM) and displayed the same
inhibitory activities as the positive control, tetramethylene glutaric acid, on rat lens aldose
reductase (Lim et al., 2003 [Korean]).
Unanaesthetized male and female cats were administered oral (p.o.) and i.p. doses of 50 and 100
mg/kg [0.18 or 0.367 mmol/kg] bw arbutin in water and observed at 0.5-, 1-, 2-, and 5-hour
intervals. Cough parameters evaluated were as follows: number of efforts, frequency, intensity
of maximum expiration and inspiration, cough effort, and intensity of cough attack in expiration
and inspiration. Arbutin at 50 mg/kg bw (i.p. and p.o.) elicited a statistically significant decrease
in the number, intensity, and frequency of coughs. Similar results were recorded for the 100
mg/kg bw i.p. and p.o. doses; an increase in antitussive activity was not observed at this dose
(Strapkova et al., 1991).
10.0 Structure-Activity Relationships
In this section, the results from NTP studies are summarized.
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Hydroquinone (HQ) [CAS No. 123-31-9]
The health effects of HQ have been extensively reviewed in IPCS Environmental Health Criteria
No. 157 and summarized in IPCS Health and Safety Guide No. 101 (IPCS, 1994, 1996).
In a two-year carcinogenesis bioassay, HQ (25 or 50, or 100 mg/kg) administered by gavage
gave some evidence of carcinogenicity in male F344/N rats (kidney tubular cell adenoma),
female F344/N rats (mononuclear cell leukemia), and female B6C3F1 mice (liver adenoma or
carcinoma). There was no evidence of carcinogenicity in male mice. Additionally, the incidence
of thyroid follicular cell hyperplasia was increased in female and male mice (NTP, 1989, 2001a,
2004a).
In Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537, HQ was negative for
mutagenicity in the presence and absence of metabolic activation (S9). In Chinese hamster
ovary (CHO) cells, it induced sister chromatid exchanges (with and without S9) and
chromosomal aberrations (with S9). HQ also induced trifluorothymidine resistance in mouse
L5178Y/TK lymphoma cells and was mutagenic in the micronucleus test. Inconclusive results,
however, were obtained in Drosophila (NTP, 1989, 2004a).
Hydroquinone Monomethyl Ether [CAS No. 150-76-5]
HQ monomethyl ether was negative in Salmonella mutagenicity assays (NTP, 2004b).
tert-Butylhydroquinone (TBHQ) [CAS No. 1948-33-0]
TBHQ (0.125, 0.25, or 0.5% [1250, 2500, or 5000 ppm]) administered in feed for lifetime
produced no evidence of carcinogenicity in male and female Fischer 344 rats and B6C3F1 mice
(NTP, 2001b, 2004c). When the rats were placed on a diet restriction (0 or 5000 ppm in feed for
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30 months), survival rates increased, while the incidences of neoplasms and nonneoplastic
lesions at various sites were maintained (NTP, 1997a. 2001c).
In S. typhimurium strains TA97, TA98, TA100, and TA102, negative results were obtained with
and without S9. TBHQ was also not mutagenic in the micronucleus test. In CHO cells, it
induced sister chromatid exchanges and chromosome aberrations in the presence of S9 only
(NTP, 1997b, 2004c).
In immunotoxicity tests, TBHQ (25, 75, or 150 mg/kg) administered via gavage to B6C3F1 mice
produced increases in the amount of the third component of serum complement, in Fc-mediated
adherence and phagocytosis by peritoneal adherent cells, and in natural killer cell activity.
Increases were also observed in liver and spleen weights, reticulocyte number, and blood glucose
increased, while a decrease in the number of neutrophils was seen (NTP, 2004c).
11.0 Online Databases and Secondary References
11.1 Online Databases
STN International Files
AGRICOLA
IPA
BIOSIS
MEDLINE
BIOTECHNO
NIOSHTIC
CABA
NTIS
CANCERLIT
Registry
EMBASE
RTECS
ESBIOBASE
TOXCENTER
National Archives and Records Administration
Code of Federal Regulations (CFR)
In-House Databases
Current Contents on Diskette®
The Merck Index, 1996, on CD-ROM
Other Databases
ChemIDplus
Dr. Duke's Phytochemical and Ethnobotanical Database
11.2 Secondary References
Budavari, S., Ed. 1996. The Merck Index, 12th ed. Merck and Company, Inc., Whitehouse
Station, NJ. CD-ROM version 12:1 1996, Chapman & Hall Electronic Publishing Division.
Lewis, R.J. 1993. Hawley’s Condensed Chemical Dictionary, 12th ed. New York, NY: Van
Nostrand Reinhold Co., p. 94.
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12.0 References
A.D.A.M., Inc. 2004. Uva Ursi. Internet address:
http://www.healthandage.com/html/res/com/ConsHerbs/Uvarursich.html. Last reviewed in April
2002. Last accessed on July 7, 2004.
Adesunloye, B.A. 2003. Acute renal failure due to the herbal remedy CKLS. American Journal
of Medicine, 9343(03):00427-3.
Ahn, K.S., Moon, K.-Y., Lee, J., and Kim, Y.S. 2003. Downregulation of NF-kappaB activation
in human keratinocytes by melanogenic inhibitors. J Dermatol Sci, 31(3):193-201. Abstract from
PubMed 12727023.
American Botanical Council. 2000. Uva Ursi leaf. Excerpt from Herbal Medicine: Expanded
Commission E Monographs (published in 1994). Internet address:
http://www.herbalgram.org/iherb/expandedcommissione/he098.asp. Last accessed on July 7,
2004.
Assaf, M.H., Ali, A.A., Makboul, M.A., Beck, J.P., and Anton, R. 1987. Preliminary study of
phenolic glycosides from Origanum majorana; quantitative estimation of arbutin; cytotoxic
activity of hydroquinone. Planta Med, 53(4):434-345. Abstract from PubMed 3671554.
Bozzuto, T.M. 2001. Antimicrobial Herbs. Internet Address: http://dcmsonline.org/jaxmedicine/2001journals/Feb2001/herbs.htm. Last updated in February 2001. Last accessed on
July 14, 2004
Burke, V., and Gracey, M. 1980. An experimental model of gastrointestinal candidiasis. J Med
Microbiol, 13(1):103-110.
Burke, V., Malajczu, A., Gracey, M., Speed, T.P., and Thornett, M.L. 1978. Intestinal transport
of monosaccharide after biliary diversion in the rat. Aust J Exp Biol Med Sci, 56(3):253-263.
Chakraborty, A.K., Funasaka, Y., Komoto, M., and Ichihashi, M. 1998. Effect of arbutin on
melanogenic proteins in human melanocytes. Pigment Cell Res, 11(4):206-212.
Choi, S., Park, Y.-I., Lee, S.-K., Kim, J.-E., and Chung, M.-H. 2002. Aloesin inhibits
hyperpigmentation induced by UV radiation. Clin Exp Dermatol, 27(6):513-515.
Chou, C.-H., and Muller, C.H. 1972. Allelopathic mechanisms of Arctostaphylos glandulosa var.
zacaensis. Am. Midland Nat, 88(2):324-347. Abstract from TOXCENTER 1973:53737.
Crane, M.F. 1991. Arctostaphylos uva-ursi. In: Fire effects Information System, U.S.
Department of Agriculture, Forest Service, Rocky Mountain Research Station, Fire Sciences
Laboratory. Internet Address: http://www.fs.fed.us/database/feis/plants/shrub/arcuva/all.html.
Last updated in February 1991. Last accessed on July 7, 2004.
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Chemical Information Review Document for Arbutin [497-76-7] and Extracts from Arctostaphylos uva-ursi
01/2006
Deisinger, P.J., Hill, T.S., and English, J.C. 1996. Human exposure to naturally occurring
hydroquinone. J Toxicol Environ Health, 47(1):31-46.
Delira, R.A., Parra-delgado, H., Apan, M.R.T. Camacho Nieto, A., and Martinez-vazquez, M.
2003. Isolation and chemical transformations of some anti-inflammatory triterpenes from Salvia
mexicana L. var. minor Benth. Rev Soc Quim Mexico 47(2):167-172. Abstract from Chem.
Abstr. 140:318007.
Deysson, G., and Truhaut, R. 1957. Influence of glucoside formation on radiomimetic activity;
comparison of hydroquinone and its glucoside, arbutoside. Comp Rendus Seanc Soc Biol Fil,
151:1719-1722. Abstract from NIOSHTIC 1997:60913.
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Acknowledgements
Support to the National Toxicology Program for the preparation of Chemical Information
Review Document for Arbutin and Extracts from Arctostaphylos uva-ursi was provided by
Integrated Laboratory Systems, Inc., through NIEHS Contract No. N01-ES-35515. Contributors
included: Scott A. Masten, Ph.D. (Project Officer, NIEHS); Marcus A. Jackson, B.A. (Principal
Investigator, ILS, Inc.); Bonnie L. Carson, M.S. (ILS, Inc.); Claudine A. Gregorio, M.A. (ILS,
Inc.); Yvonne H. Straley, B.S. (ILS, Inc.); Nathanael P. Kibler, B.A. (ILS, Inc.); and Barbara A.
Henning (ILS, Inc.).
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Chemical Information Review Document for Arbutin [497-76-7] and Extracts from Arctostaphylos uva-ursi
Appendix A: Units and Abbreviations
ºC = degrees Celsius
µg/L = microgram(s) per liter
µg/m3 = microgram(s) per cubic meter
µg/mL = microgram(s) per milliliter
µM = micromolar
BLDE = bearberry leaves dry extract
bw = body weight
FDA = Food and Drug Administration
g = gram(s)
g/mL = gram(s) per milliliter
GI = gastrointestinal
h = hour(s)
HPLC = high performance liquid chromatography
HQ = hydroquinone
i.g. = intragastric
i.p. = intraperitoneal(ly)
kg = kilogram(s)
L = liter(s)
lb = pound(s)
LC50 = lethal concentration for 50% of test animals
LD50 = lethal dose for 50% of test animals
M = molar
mg/kg = milligram(s) per kilogram
mg/m3 = milligram(s) per cubic meter
mg/mL = milligram(s) per milliliter
min = minute(s)
mL/kg = milliliter(s) per kilogram
mm = millimeter(s)
mM = millimolar
mmol = millimole(s)
mmol/kg = millimoles per kilogram
mol = mole(s)
mol. wt. = molecular weight
NIEHS = National Institute of Environmental Health Services
NIOSH = National Institute for Occupational Safety and Health
n.p. = not provided
NTP = National Toxicology Program
OTC = over-the-counter
PC-CD = picryl chloride-induced contact dermatitis
p.o. = per oral(ly)
ppm = parts per million
RTECS = Registry of Toxic Effects of Chemical Substances
SRBC-DTH = sheep red blood cell delayed type hypersensitivity
TBHQ = tert-butylhydroquinone
UV = ultraviolet
23
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Appendix B: Description of Search Strategy and Results
Arbutin (4-Hydroxyphenyl-β-D-glucopyranoside; Hydroquinone-β-D-glucopyranoside;
Arbutoside) (CAS RN 497-76-7; ILS CODE X0110) and
Extracts from Arctostaphylos uva-ursi (Bearberry, Upland Cranberry, etc.)
Nomination
Arbutin is a common ingredient in dietary supplements, cosmetics and dermatological
preparations for skin lightening (inhibits conversion of tyrosine to melanin), and pharmaceutical
preparations, particularly for urinary tract infections (in other countries). It occurs in certain
foods and beverages of a normal North American diet, being found in the leaves of many other
species and in other plant parts (e.g., pear fruits). Arbutin hydrolysis gives hydroquinone (HQ)
(excreted by mammals primarily in the urine as the sulfate and glucuronide) from enzymatic
cleavage in mammals and certain bacteria (capability of arbutin hydrolysis is commonly used in
a battery of tests for characterization of bacterial species). Additional cleavage by Escherichia
coli to hydroquinone may occur in the urinary tract (primarily during symptomatic urinary tract
infections) and increase the concentration of free HQ in urine. In NTP testing in rodents, HQ
induced renal tubule and liver adenomas and thyroid gland follicular cell hyperplasia. [IARC
(vol. 71, 1999) stated HQ has limited evidence for carcinogenicity in animals and assigned it to
Group 3.]
Search Strategy
An initial search in PubMed (free MEDLINE) for arbutin OR uva-ursi (and plant synonyms) was
done on May 27, 2004, retrieving 274 records. The Chemical Information System, searched with
the CAS RN on May 18 resulted in a few additional records from SANSS, DATALOG,
PHYTOTOX, and AQUIRE. On July 9, 2004, a simultaneous search of MEDLINE,
CANCERLIT, AGRICOLA, NIOSHTIC, EMBASE, CABA, ESBIOBASE, BIOTECHNO,
BIOSIS, IPA, TOXCENTER, and NTIS was done using as search terms the CAS RN (889
records) and several chemical synonyms listed in the Registry file record. Several synonyms for
Arctostaphylos uva-ursi were also used. The search strategy for the online session is shown in
Attachment A. The numbers of records per STN International database were as follows
(numbers of records printed in full from the database are in parentheses; practically every patent
in the first 700 alphabetically sorted titles was printed):
268
3
136
284
164
5
33
316
160
6
ANSWERS
ANSWERS
ANSWERS
ANSWERS
ANSWERS
ANSWERS
ANSWERS
ANSWERS
ANSWERS
ANSWERS
'1-268' FROM FILE MEDLINE (3)
'269-271' FROM FILE NIOSHTIC (3)
'272-407' FROM FILE AGRICOLA (40)
'408-691' FROM FILE CABA (68)
'692-855' FROM FILE EMBASE (69)
'856-860' FROM FILE ESBIOBASE (0)
'861-893' FROM FILE IPA (20)
'894-1209' FROM FILE BIOSIS (58)
'1210-1369' FROM FILE TOXCENTER (72)
'1370-1375' FROM FILE NTIS (2)
Several Internet searches with the Google search engine were done using multiple strategies.
Specific Internet searches included the Phytochemical and Ethnobotanical Databases, the Fire
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Effects Information System (FEIS) (Forest Service), CFR titles 21, 29, and 40, the FDA and
USDA websites, PubMed Central, ChemIDplus, TOXLINE core, and DART. The bulk of the
information retrieved from the Internet was on commercial dietary supplements and cosmetics
and reviews from various health- and plant-related web sites. The URLs for many documents
retrieved during the Internet searches are listed in Attachment B.
Search Results
Search results are grouped numerically by ILS subject code (shown by the major headings in the
discussion below) and by subgroups (with or without ILS subject codes). Within the groups, the
database records and other pages are organized alphabetically (first author surname, company
name, or publication name).
Reviews (Subject Codes 05/11)
About 25 items are in this group; some are only citations from reviews found on the Internet.
Some of the more notable reviews included are the American Botanical Council (2000)
Expanded Commission E Monograph; Clifford (2000), who provided a critical review of phenols
in foods and beverages; Crane (1991); ESCOP (European Scientific Cooperative on
Phytotherapy) (1997); Kemper (1999) (15 pp., 63 refs.); Rook (2004); and Simonet (2000).
ESCOP recommended that uva ursi be used for “uncomplicated infections of the urinary tract
such as cystitis when antibiotic treatment is not considered essential” (Sharp Labs., Inc., USA,
2002).
Chemical Identification (13a)
This group contains about 50 items, including 18 from the Internet, 19 from STN International
biomedical databases, and 9 from PubMed. ChemIDplus, SANSS, and Registry records and
pages from the Phytochemical and Ethnobotanical Databases are included. Topics in the
biomedical database records include other A. uva-ursi constituents, descriptions of plant
morphology and growth habits, and photographic images. Other constituents of A. uva-ursi
leaves and their extracts include methylarbutin (also found in the roots), gallic acid, tannins,
gallotannins, flavonoids, piceoside, and ursolic acid. See especially the Phytochemical Database
listing of multiple constituents besides arbutin.
Chemical-Physical Properties (13b)
This group contains 16 items (7, STN Int.; 6, PubMed; 2, Internet; and 1, TOXLINE). Properties
included are taste, polymorphism, and hydration. Reactions studied included hydrolysis,
thermodegradation, photostability, storage stability of extracts, color reactions, and reduction.
Analytical Methods (13c)
This group contains 27 STN International records and 14 PubMed records. Other papers
including mention of analytical methods are distributed throughout the package. No directed
search for analytical methods was done in CAPLUS. Modern methods for arbutin determination
in crude drugs, plant tissues and fluidextracts, and cosmetics include HPLC with UV or diode
array detectors, planar and [?] high performance thin layer chromatography, spectrophotometry,
and capillary zone electrophoresis.
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Commercial Availability (01a/b) [Producers (01a)/Suppliers (01b)]
This group contains 33 items from Internet searches. Many are from individual suppliers of
consumer dietary supplements. Some websites such as amazon.com returned lists of retail or
wholesale suppliers. Some of the 133 uva-ursi health products listed by amazon.com were from
the following suppliers (number of products in parentheses):
Eclectic Institute (23)
Gaia Herbs (14)
Nature's Way (12)
Nature's Herbs (4)
Nature's Answer (4)
Herb Pharm (4)
Planetary Formulas (3)
Solaray (3)
betterlife com (3)
Planetary Formulations (2)
Health From The Sun (2)
NATURE'S WAY (2)
Nature's Way Herbal Singles (1)
Nature'S Herbs (1)
Nature'S Way (1)
Searches for bulk suppliers found companies such as Peakchem and Organic Herbs Inc. in China
and Richmond Chemicals in the USA. Searches of CHEMCATS, PROMT, CIN, and CEN would
provide more trade information.
Production Processes (01d)
Approximately 70 database records or other items are included in several subgroups:
• 01d: Arbutin Synthesis from Hydroquinone Added to Tissue Cultures of Other Species
(16 records; 4 from PubMed, and 12 from fee-based databases)
• 01d: Pharmaceutical Extractions (15 records)
• 01d: Arbutin Enzymatic Synthesis (3), Arbutin Biosynthesis (3), and α-arbutin synthesis
(3)
• 01d: Other Arbutin Preparation Processes: Preparation from Acylated Arbutins (2
patents), Reducing Microbiological Contamination (1), Bergenia Leaves as A. uva-ursi
Substitute Source for Arbutin (1), and Drying and Shredding A. uva-ursi Leaves (1)
• 01d: Agricultural Production and Harvesting from the Wild (3) [See also Musil et al.
(1988) in Group 13a.]
• 01d: Plant Propagation Methods: Hydroponics (1); Tissue Culture (2); Seminatural
Cultivation (1); Habitat Revival/Restoration (3); and 15 on Cultivation for Ornamental
Use, Growth in Greenhouses, Use of Cuttings, and Effects of Irradiation
The origins for the first 50 records (all but the last subgroup) were tallied: 34 records from STN
International databases, 1 from TOXLINE, 7 from PubMed, and 8 from the Internet.
Production and Import Volumes (01c)
Traffic (the Wildlife Trade Monitoring Network) (undated) reported that A. uva-ursi has not been
cultivated, indicating that plant material in trade is from wild sources. No statistics are available for
annual demand for the leaves (sold dry, cut or whole).
Other Processes (01e)
One to three papers in other groups have been coded 01e. No specific group is included in this
package.
Uses (01f)
Industrial uses of arbutin such as in photography and polymer science [not yet confirmed by ILS
search of CAPLUS] are mentioned in Hawley’s Condensed Chemical Dictionary (Lewis, 1993).
The ~70 items in this group are primarily from searches of the biomedical databases and the
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Internet. Treatment for urinary tract infections and skin-lightening dermatological and cosmetic
formulations predominate. Uva-ursi is used in naturopathic (e.g., Abascal and Yarnell, 2002) and
homeopathic remedies (e.g., abchomeopathy.com, 2002). Arbutin is used in biochemical
identification of strains of microorganisms [arbutin hydrolysis test] (e.g., Aldova et al., 1994).
(Only a few examples of this use from the search results are included in the package.) Permitted
food additive use of arbutin or A. uva-ursi extracts was not confirmed (e.g., ILS would need to see
Anonymous, 2002 [Swiss food legislation] and DaVincenzi et al., 1997); but a few articles studied
the antioxidant abilities against food-contaminating microorganisms (e.g., Amarowicz et al., 2004).
α-Arbutin is produced synthetically and has been found to be an order of magnitude more effective
than arbutin as a skin-lightening compound for skin care products (e.g., Aoyama, 2001).
Environmental Releases, Occurrence, and Fate (04)
Approximately 60 records are included in this group. Time did not permit actual subgrouping. A
large fraction of these studies report finding arbutin in other plants. (This is not a comprehensive
collection; many records in the STN International results were not selected for printing.) Arbutin
was a metabolite of the herbicide ioxynil (1,6-diiodo-4-cyanophenol) in barley roots, but not
spinach leaves (Berűter, 1971). Its rate of photooxidation in aqueous solution has been determined
(Buxton et al., 1988). It occurs in soils and leaf litter and is phytotoxic (allelopathic) (e.g., Chou
and Muller, 1972; Saario et al., 2002). It is hydrolyzed by fungi (e.g., Demetriades and Emmanouil,
1971) and snails (e.g., Hryk et al., 1992), which suggests possible biodegradation when released to
soil. Several sources described the geographical distribution of A. uva-ursi in the USA (e.g.,
Douglas and Bliss, 1977; Johnson and Wyatt, 2004; Rosatti, 1987, 1988; USDA NRCS, 2002).
Arbutin has been reported in air particulates, presumably in pollen (Inglett and Lodge, 1959; Li et
al., 2002). Malovic (1953) reported that “addition of arbutine substances to the soil increased the
acidity of soil and exhibited on [sic] adverse effect upon the growth of higher plants.” The
Phytochemical and Ethnobotanical Databases list plants with arbutin (edible plant parts include
rosemary leaves and bilberry fruits). A report by Russian authors suggests that arbutin may be
found in sewage [or industrial effluents discharged to sewers?] (Stom et al., 1992).
Exposure Potential (02)
Items are grouped as follows:
• Subgroup 02: Natural Foods [19 records (PubMed and STN). Arbutin-containing foods
include marjoram; pears (fruit, juice, possible adulterant in quince products); multiple foods
and beverages (Deisinger et al., 1996); foods of Native Canadians; Japanese pepper;
potatoes (Solanum tuberosum) infected with fungi (Keller et al., 1996; Schmidt, 1969 diss.);
and honeys in Italy and Sardinia. McDonald et al. (2001) hypothesized that “Phenol and
hydroquinone derived mainly from diet and gastrointestinal flora activity are causal factors
of leukemia.”]
• Subgroup 02: Potential as Food Additive [5 records (4 STN, 1 Internet). Two of the
studies were from the Department of Applied Microbiology, University of Saskatchewan
(Dykes et al., 2003b; Pegg et al., 2003 abstr.) [See also Dykes et al. (2003b) in Group 22.]
The antioxidant and antimicrobial properties of A. uva-ursi extracts are discussed in the 4
journal articles.]
• Subgroup 02: Dietary Supplements, Pharmaceuticals, Skin Care Products, and Internal
Cleansers [5 items (2 STN, 1 PubMed). Representatives on the first three topics are, of
course, in other groups in this package. Renew Life Formulas, Inc., USA, has patented an
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•
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herbal intestinal tract cleanser containing uva ursi, several other herbs, and magnesium
caprylate (Watson and Watson, 2003 patent). This is probably a laxative taken orally or
perhaps as a suppository, not an irrigation product. Oral and dermal appear to be the major
routes of consumer exposure to arbutin.]
Subgroup 02: Occupational Exposure [This group comprises multiple web pages from the
National Occupational Exposure Survey (1981-1983), a CDC website. About 2600 workers
(595 female) were potentially exposed to uva ursi in the Chemicals and Allied Products
industry (SIC 28). A breakdown by occupation indicates that nearly half of the workers
operated packaging and filling machines. Another product exposure category is uva ursi
powdered extract, which is apparently a subset of the uva ursi data. For example, the
number involved in operating grinding and similar machines (357) was the same in each
category. Dermal, inhalation, and unwashed hand-to-mouth contact are likely occupational
exposure routes.]
Subgroup 02: Free Hydroquinone in Urinary Tract [3 PubMed records. Siegers et al.
(2003) reported that E. coli takes up, enriches, and metabolizes HQ glucuronides and
sulfates to hydroquinone. Thus, urine of persons with urinary tract infections caused by E.
coli (common) and treated with arbutin-containing preparations would be expected to have a
higher ratio of free to conjugated HQ than that of persons eating a normal arbutin-containing
diet. Note that viable E. coli have been found in the urine of humans and mice without
urinary tract infections (Anderson et al., 2004; Schlager et al., 2003). The urine was drawn
directly from the bladders of the mice.]
Regulations (24)
Bearberry is not generally recognized as safe and effective. In October 1990, FDA proposed to ban
the use of 111 ingredients, including bearberry, in nonprescription diet drug products (FDA, 1990
press release). When the ban became effective, uva ursi-potassium extract was specifically named
(FDA, 1991 press release). The use of bearberry (extract of uva ursi) and bearberry fluid extract
(extract of bearberry) was included among ingredients in a proposed ban from nonprescription
orally administered menstrual drug products (FDA, 1992 press release). FDA (1999, 2000) list
product recalls for distribution without approved new drug applications. In the OTC Ingredient List
Updated July 2003, the use of bearberry as an anorectic for weight control is regulated under 21
CFR 310.545(a)(20) and the use of bearberry (extract of uva ursi) and bearberry fluidextract
(extract of bearberry) as a “menstrual/diuretic” is regulated under 21 CFR 310.545(a)(24)(Shustov
and I). [Attempts to retrieve pdf copies of the CFR sections have not been successful.] The FDA
Veterinarian (FDA CVM, 2000) noted that A. uva-ursi is an unapproved herb currently marketed
for use in animals as a diuretic and urinary antiseptic.
Human Data (18) (Including Human Metabolism)
This group contains 24 records (9 PubMed, 12 STN Int., 3 Internet). The studies include clinical
efficacy (10), metabolism (9), adverse effects/case studies (4), and a study of the antioxidant
activity (biopsy specimens?).
ADME (12)
About 40 items are in this group (24 PubMed, 10 STN Int., 3 Internet). Human metabolism studies
are in Group 18. Studies in Group 12 include studies of intestinal absorption and arbutin transport
(e.g., Alvarado, 1965; Lostao et al., 1994); bacterial utilization (e.g., Brown and Thomson, 1998);
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effects of bile salts on sugar uptake (e.g., Gracey et al., 1973); erythrocyte permeability (Matsumoto
et al., 1989, 1991, 1993); dermal absorption (Takeoka et al., 2003 pat. appl.); and rat urinary
metabolites (Temple et al., 1971 [French]).
Acute Toxicity (03)
One Chinese study of the antitussive effect of arbutin at oral and i.p doses up to 200 mg/kg in mice
apparently included some short-term pharmacological experiments (Li et al., 1982). The
TOXCENTER/CA abstract stated that its antitussive effect was as potent as that of codeine
phosphate, but arbutin had no analgesic or anesthetic effects. Arbutin had no effect on tracheal
smooth muscle contraction, respiratory activity, spontaneous behavior, blood pressure, or heart rate
and electrical activity.
Short-Term and Subchronic Toxicity (06a)
No group 06a is in the package. When Li et al. (1982) (in Group 03) dosed mice with 8 g
arbutin/kg i.p. (acute study?) and dosed monkeys with 50 mg/kg/day for 2 weeks, they did not
observe any toxicity. Some other subchronic studies may have been done with animal models of
disease, but these are placed in a separate code 14 subgroup with other short-term studies of
therapeutic actions.
Chronic Toxicity (06b)
No group 06b is in the package. No long-term studies were found.
Antagonisms and Synergisms (22)
Four studies are in this group (3 PubMed, 1 STN Int.). Ahn et al. (2003) studied in vitro inhibition
of UV-induced NF-kappaB activation. An A. uva-ursi extract, considered for food preservation
use, enhanced the antimicrobial activity of nisin (Dykes et al., 2003a). Arbutin and A. uva-ursi
extract increased the potency of prednisolone in inhibition of swelling due to contact dermatitis in
mice (Kubo et al., 1990). [See other anti-inflammatory studies in Group 08.] Arbutin counteracted
oxidative stress induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in mouse skin (Nakamura
et al., 2000).
Reproductive and Developmental Toxicity (10)
Itabashi et al. (1988) (Japanese) studied the effect of arbutin in subcutaneous doses up to 400
mg/kg/day on the reproductive performance of parent rats and the development and reproductive
performance of F1 rats. The maximum no-effect dose was 100 mg/kg/day. According to the
RTECS record, some fetotoxicity and reproductive effects on the dams and/or offspring were noted.
Carcinogenicity (07a) and Co-Carcinogenicity (07b)
No studies were found.
Anticarcinogenicity (07c)
Several in vitro studies are in this group of 7 records from STN International databases. One study
used tannins isolated from A. uva-ursi (Kakiuchi et al., 1985) and another used its galloyl
glycosides (Saeki et al., 2000). Extracts were tested for antitumor activity in numerous in vitro
screening systems by Itokawa et al. (2000) as well as in mice with Sarcoma 180A and P388
lymphocytic leukemia.
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Genotoxicity (09a)
Two of the 3 records in this group are from STN International databases. Deysson and Truhaut
(1957) studied cytotoxicity, growth inhibition and stimulation, and DNA damage in arbutin-treated
garlic (Allium sativum) roots. Uva-ursi extracts were negative in micronucleus tests with human
peripheral blood lymphocytes (Joksic et al., 2003). Műller and Kasper (1996 abstr.) studied
micronucleus formation in mice and mutations in hamster V79 cells.
Immunotoxicity (08)
Half of the 10 records in this group are from STN International databases and the rest are from
PubMed. Studies include effects on polymorphonuclear leukocytes and peritoneal macrophages;
skin sensitization potential using the murine local lymph node assay (LLNA); synergistic antiinflammatory effects in combination with prednisolone, dexamethasone, or indomethacin in mice;
and the mechanism of allergic cross-reactions.
Other Biological Activities (14)
The folders in these subgroups contain a total of 92 biomedical database records (50 from
PUBMED, 3 from TOXLINE, and 39 from STN International databases). Total records in each
folder are shown in parentheses.
• Subgroup 14-23. Effects on Membranes (3)
• Subgroup 14-28. Effects on Enzymes: Tyrosinase and Inhibition of Melanogenesis (37)
[These studies are on the skin-lightening effect. Arbutin is often used as a positive control
when comparing other skin-lightening agents.]
• Subgroup 14-28. Effects on Enzymes: P-450 (1)
• Subgroup 14-30. Effects on Blood: Anticoagulant and Hypoglycemic (6)
• Subgroup 14. Antioxidant and Free Radical Scavenger (7)
• Subgroup 14. Therapeutic Efficacy in Animal Models, Especially Models of Disease
(Other Than Diabetes and Arthritis/Inflammation) (9)
• Subgroup 14. Cholegogue and Choloretic Activity (3) [“MESH Database definition:
Gastrointestinal agents that stimulate the flow of bile into the duodenum (cholagogues) or
stimulate the production of bile by the liver (choleretic).”]
• Subgroup 14. Uterotonic Activity [Bearberry leaf infusions did not show uterotonic
activity in isolated guinea pig and rabbit uterine horn (Shipochliev, 1981).]
• Subgroup 14. Antimicrobial Activity (9)
• Subgroup 14. Aquatic Toxicity (3) [Tests on brine shrimp and Daphnia are used to screen
phytochemicals for biological activity. See tests with algal species in the next subgroup.]
• Subgroup 14. Phytotoxicity and Other Effects on Plants (14)
Structure-Activity Relationships (25)
Subgroup 25: Hydroquinone
IPCS (1994) reviewed HQ health effects in Environmental Health Criteria 157. IPCS (1996) is a
Health and Safety Guide for HQ. In a two-year carcinogenesis bioassay, HQ administered by
gavage gave some evidence of carcinogenicity in male (MR) and female rats (FR) and female mice
(FM) (NTP HQ testing status report, 1994). Neoplastic lesions were kidney tubular cell adenoma
(MR), mononuclear cell leukemia (FR), and liver adenoma and some carcinoma (FM). MM and
FM exhibited thyroid gland follicular cell hyperplasia (NTP Target Organs, 2001; NTP TR-366,
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1989). The RTECS record for HQ lists several reproductive effects studies, primarily in rats, and
numerous in vitro and in vivo genotoxicity assays. DeCaprio (1999) published a 48-page review on
the toxicology of hydroquinone; the most serious effect in humans is pigmentation of the eye,
which may cause corneal damage.
Subgroup 25: Hydroquinone Monomethyl Ether; p-Hydroxyanisole
The compound was negative in NTP-sponsored Salmonella mutagenicity assays (NTP testing status
report, 2004).
Subgroup 25: tert-Butylhydroquinone (TBHQ)
ILS prepared an NTP-sponsored genotoxicity review for this compound ca. 1994. TBHQ gave
positive results in in vitro studies of chromosome aberrations and sister chromatid exchanges. There
was no evidence of carcinogenicity in a 2-year bioassay (dosed-feed) (NTP testing status report,
2004; NTP TR-489, 1997). In an NTP-sponsored immunology study, mice showed elevated natural
killer cell activity and increased phagocytosis and adherence of cRBC (NTP, undated).
Subgroup 25: Analogs from Budavari (1996)
Subgroup 25: Analogs from ChemIDplus
Only one analog, α-arbutin, was returned with the 4-hydroxyphenyl moiety in the top 15 results of a
similarity search. 4-Hydroxyphenyl-O-xyloside was within the top 50. Some other arbutin
glycosides were mentioned from another plant (the record is not in this group).
Subgroup 25: Analogs from the STN International REGISTRY File
Subgroup 25: Other Studies
Many of the studies on the effects on tyrosinase/melanogenesis compared arbutin with other plant
constituents. Some were glycosides, but they did not have a 4-hydroxyphenyl moiety. Hamid et al.
(2004) studied the effect of deoxyarbutin on melanogenesis in mice. Yamashita et al. (1993) found
methoxy analogs of arbutin in cane molasses and compared their tyrosinase inhibition activity with
that of arbutin. Glycoside binding and translocation studies compared arbutin and phenylglucose
(Diez-Sampedro et al., 2000) and arbutin and other phenylglucosides (Lostao et al., 1994).
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